The endocannabinoid system (ECS), which includes endogenous cannabinoids, their receptors, and the enzymes involved in the biosynthesis and degradation of endocannabinoids, plays an important role in the control of body weight and energy homeostasis. In several large clinical trials, the CB1 receptor (CB1R) blocking drug rimonabant had been found effective in reducing body weight and improving cardiometabolic abnormalities in patients with the metabolic syndrome, but was recently withdrawn from the market due to neuropsychiatric side effects, including depression, anxiety and suicidal ideation. We had earlier provided evidence that the liver is a major target of the metabolic effects of endocannabinoids in mice with diet-induced obesity (DIO)(JCI 115:1298, 2005). In a subsequent study using mice with liver-specific knockout of CB1R we have demonstrated that activation of hepatic CB1R contributes to steatosis, insulin and leptin resistance as well as dyslipidemias, but not to increased adiposity (JCI 118:3160-69, 2008). Functional CB1R are also present in adipocytes, skeletal muscle and pancreatic beta cells, raising the possibility that peripheral CB1 receptors may be targeted for the treatment of fatty liver, impaired glucose homeostasis, and dyslipidemia in order the minimize the neuropsychiatric side effects of non-selective CB1 blockade during the treatment of obesity-associated conditions. In a collaborative study with Alex Makriyannis (Northeastern Univ., Boston), we have developed a peripherally restricted CB1R antagonist. AM6545 is a novel, orally bioavailable CB1R neutral antagonist with high CB1R binding affinity similar to that of the brain-penetrant CB1R antagonist rimonabant. AM6545 has markedly reduced brain penetrance, with a brain to plasma ratio of 0.03 compared to 0.76 for rimonabant. Unlike rimonabant, AM6545 fails to inhibit central CB1R-mediated increases in locomotor activity or cataleptic behavior, and does not induce anxiety-related behaviors in mice. On the other hand, AM6545 has effects similar to rimonabant on hormonal/metabolic parameters in mice with diet-induced obesity (DIO). Treatment of DIO mice with 10 mg Kg-1 day-1 AM6545 for 28 days significantly reduced body weight without an overall effect on caloric intake, by shifting energy expenditure from carbohydrate to fat oxidation. Elevated serum leptin, glucose and insulin levels were significantly reduced or normalized, while adiponectin levels increased. AM6545 treatment ameliorated glucose tolerance and insulin sensitivity. Finally, AM6545 treatment fully reversed the diet-induced hepatic steatosis and hepatocellular damage, as well as CB1R-mediated de novo hepatic lipogenesis. Thus, selective blockade of peripheral CB1R is sufficient to improve the metabolic abnormalities associated with obesity, which suggests that non brain-penetrant CB1R antagonists may have value in the treatment of these disorders in humans. These findings have been written up for publication. Our earlier findings using hepatocyte-specific CB1R knockout mice indicated that hepatic CB1R are necessary for diet-induced steatosis, insulin and leptin resistance and dyslipidemias to develop in mice. To address the question whether activation of hepatic CB1R is sufficient for these effect, we have developed a rescue model, transgenic mice that express CB1R only in hepatocytes. This was achieved by transfecting fertilized egges of CB1R knockout mice with a construct of the mouse CB1R driven by the mouse albumin promoter. We have established several lines with variable degrees of CB1R expression in hepatocytes and verified the absence of CB1R in all other tissues. When fed a high fat diet, these mice remained lean, but developed glucose intolerance and insulin resistance. Also, glucose intolerance and insulin resistance can be acutely induced by the ip injection of the endocannabinoid anandamide in wild-type and liver CB1R transgenic mice, but not in CB1R-/- or hepatocyte-specific CB1R-/- (LCB1R-/-) mice. In collaboration with Christoph Buettner at Mount Sinai School of Medicine in NY, we performed hyperinsulinemic, euglycemic clamps in conscious wild-type, CB1R-/- and LCB1R-/- mice. High fat diet resulted in a marked suppression of the glucose infusion rate in wild-type mice but not in either knockout strain, with no change in tracer glucose uptake into adipose tissue or skeletal muscle. This indicates that high fat diet caused selective hepatic insulin resistance via activation of hepatic CB1R. Endocannabinoids and CB1 receptors are essential components of the mesolimbic dopaminergic reward pathway, and CB1 receptor blockade was found to disrupt drug-seeking behavior, including voluntary alcohol drinking in rodent models. Based on such findings in animal studies, including our own, we have completed a phase I/II clinical trial to assess the safety of rimonabant treatment in young, heavy drinking subjects and its efficacy to reduce their desire to drink. This was a double-blind, placebo controlled study involving forty heavy drinking subjects (consuming between 20 and 50 drinks per week) between the ages of 21 and 45 years who took rimonabant (20 mg/day) or placebo for two weeks, followed by an in-hospital laboratory drinking paradigm where their desire to drink as well as their physiological, psychological and hormonal response to exposure to alcohol and drinking was evaluated. Results from both the outpatient call-ins and the alcohol self-administration paradigm failed to show a statistically significant difference between those receiving rimonabant or placebo. This suggests that the daily administration of 20 mg rimonabant for two weeks has no effect on alcohol consumption in heavy social drinkers. A manuscript summarizing these results is under consideration for publication in Psychopharmacology.